ABSTRACT - Project 3: Impact of combined medication and behavioral treatment in young children with comorbid ASD and ADHD Children with comorbid autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) have significantly worse outcomes than those with either ASD alone or ADHD alone. Currently, effective early treatment approaches that take into account the presence of ADHD symptoms have not been developed for young children with ASD. The overarching goals of Project 3 are to (1) evaluate a novel early intervention model personalized for young children with ASD+ADHD that pharmacologically addresses ADHD symptoms prior to initiating early behavioral intervention; and (2) identify changes in behavioral and neurophysiological activity that may underlie improved outcomes in children with comorbid ASD and ADHD. We will accomplish these goals by systematically evaluating whether stimulant treatment augments the efficacy of a parent- delivered behavioral intervention based on the Early Start Denver Model (P-ESDM). Children with ASD+ADHD will be randomized to receive either an extended release amphetamine product (Adzenys-XR-ODT; AMP) or placebo prior to initiating early behavioral intervention. The flexibly dosed AMP or placebo will be provided for 30 weeks under double-blind conditions. P-ESDM will consist of individual parent coaching provided for 90 minutes weekly for 24 weeks beginning six weeks after AMP or placebo is initiated. The primary outcomes will be frequency of joint attention initiations, a core ASD symptom, and social and communicative functioning assessed with the Vineland Adaptive Behavior Scales. Our primary hypothesis is that reducing ADHD symptoms prior to and during P-ESDM will facilitate initial and sustained attention of children with ASD+ADHD to P-ESDM activities, leading to more engagement in and greater benefit from P-ESDM, reflected in greater improvements in joint attention and social and communicative functioning. Secondary aims are to determine the efficacy for improving ADHD symptoms, assessed with the ADHD-Rating Scale, and tolerability of Adzenys-XR-ODT in young children with ASD+ADHD. We will also determine the association between changes (pre- and post-treatment) in joint attention, social and communicative functioning, and ADHD symptoms and changes in social attention (assessed via an eye-tracking biomarker) and sustained social engagement with caregiver (assessed via structured observations of parent-child interaction). Finally, we will examine the association between changes in outcomes and changes in neurophysiological measures of neural connectivity and neural stability (EEG coherence and intertrial phase coherence) and responsiveness to social stimuli (event-related brain potentials). If significant beneficial effects of combined stimulant and behavioral treatment on children's outcomes are demonstrated, Project 3 will significantly inform current clinical treatment of young children with co-morbid ASD and ADHD, which could potentially mitigate the negative impact of co- occurring ADHD symptoms on outcomes of children with ASD.